The central problem this work addresses is how cells communicate their fitness and recognize aberrant fitness differences that might endanger growing tissues. Much evidence indicates that the recognition of fitness disparities elicits interactions that prevent the weaker cells from contributing to the animal, promoting optimal tissue and organismal fitness. Cell competition is a mechanism that facilitates this homeostatic process, and is initiated upon recognition of cells perceived as less fit by their more robust neighbors. Examples of competitive behavior between cells of different fitness are numerous, but the best studied those induced by reduced ribosomal proteins (Rp), or reduced or enhanced expression of the transcription factor Myc. The developing Drosophila wing is the critical paradigm for study of cell competition - as a model system it is unsurpassed for mosaic studies of cell-cell interactions in living animals, and offers unparalleled genetic and molecular toolkits. We recently discovered that communication between the ?winner? and ?loser? cells is mediated by a novel signaling pathway consisting of components co-opted from the highly conserved innate immune response pathways. Our long-term goal is to explore both proximate (how does this work) and ultimate (what is it for) questions about cell competition. In this proposal, we focus on three major quests: 1), to further explore the mechanism by which signal activation is controlled and restricted to only nearby ?loser? cells; 2) to delineate the endogenous role of cell competition during normal animal physiology; and 3) to investigate the existence of a general mechanism of cell fitness sensing. !